Piperidine and morpholine derivatives and their use as therapeutic agents

ABSTRACT

The present invention provides compounds of formula (I), wherein R 1  is phenyl or a 5- or 6-membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which aryl or heteroaryl group is optionally substituted; R 2  is hydrogen, halogen, C 1-6  alkyl, C 1-6  alkoxy, CF 3 , OCF 3 , NO 2 , CN, SR a , SOR a , SO 2  R a , CO 2  R a , CONR a  R b , C 2-6  alkenyl, C 2-6  alkynyl or C 1-4  alkyl substituted by C 1-4  alkoxy, where R a  and R b  each independently represent hydrogen or C 1-4  alkyl; R 4 , R 5 , R 6 , R 9a  and R 9b , A, X, and Y are as defined in the specification; the dotted line is an optional double bond; Q 1  is oxygen, sulphur or --NH--; Q 2  is --N═, --NH--, --CH═ or --CH 2  --; and m is zero or 1; and pharmaceutically acceptable salts and prodrugs thereof. The compounds are of particular use in the treatment or prevention of pain, inflammation, migraine, emesis and postherpetic neuralgia. ##STR1##

This application is a 371 of PCT/GB96/01477 filed Jun. 20, 1996.

This invention relates to a class of aromatic compounds which are usefulas tachykinin antagonists. More particularly, the compounds of theinvention contain an amnine-substituted azo-heterocyclic moiety.

The tachykinins are a group of naturally occurring peptides found widelydistributed throughout mammalian tissues, both within the centralnervous system and in peripheral nervous and circulatory systems.

At present, there are three known mammalian tachykinins referred to assubstance P, neurokinin A (NKA, substance K, neuromedin L) andneurokinin B (NKB, neuromedin K) (for review see J. E. Maggio, Peptides(1985) 6(suppl. 3), 237-242). The current nomenclature designates thethree tachykinin receptors mediating the biological actions of substanceP, NKA and NKB as the NK₁, NK₂ and N₃ receptors, respectively.

Evidence for the usefulness of tachykinin receptor antagonists in pain,headache, especially migraine, Alzheimer's disease, multiple sclerosis,attenuation of morphine withdrawal, cardiovascular changes, oedema, suchas oedema caused by thermal injury, chronic inflammatory diseases suchas rheumatoid arthritis, asthma/bronchial hyperreactivity and otherrespiratory diseases including allergic rhinitis, inflammatory diseasesof the gut including ulcerative colitis and Crohn's disease, ocularinjury and ocular inflammatory diseases, proliferativevitreoretinopathy, irritable bowel syndrome and disorders of bladderfunction including cystitis and bladder detruser hyper-reflexia isreviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists",C. A. Maggi, R. Patacchini, P. Rovero and A Giachetti, J. Auton.Pharmacol. (1993) 13, 23-93.

For instance, substance P is believed inter alia to be involved in theneurotransmission of pain sensations [Otsuka et al, "Role of Substance Pas a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34(published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Actas a Pain Transmitter?" TIPS (1987) 8, 506-510], specifically in thetransmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem,(1982) 25, 1009) and in arthritis [Levine et al Science (1984) 226,547-549]. Tachykinins have also been implicated in gastrointestinal (GI)disorders and diseases of the GI tract such as inflammatory boweldisease [Mantyh et al Neuroscience (1988) 25(3), 817-37 and D. Regoli in"Trends in Cluster Headache" Ed. Sicuteri et al Elsevier ScientificPublishers, Amsterdam (1987) page 85)] and emesis [F. D. Tattersall etal, Eur. J. Pharmacol., (1993) 250, R5-R6]. It is also hypothesised thatthere is a neurogenic mechanism for arthritis in which substance P mayplay a role [Kidd et al "A Neurogenic Mechanism for SymmetricalArthritis" in The Lancet, Nov. 11, 1989 and Grbnblad et al,"Neuropeptides in Synovium of Patients with Rheumatoid Arthritis andOsteoarthritis" in J. Rheumatol. (1988) 15(12), 1807-10]. Therefore,substance P is believed to be involved in the inflammatory response indiseases such as rheumatoid arthritis and osteoarthritis, and fibrositis[O'Byrne et al, Arthritis and Rheumatism (1990) 33, 1023-8]. Otherdisease areas where tachykinin antagonists are believed to be useful areallergic conditions [Hamelet et at, Can. J. Pharmacol. Physiol. (1988)66, 1361-7], immunoregulation [Lotz et al, Science (1988) 241, 1218-21and Kimball et al, J. Immunol. (1988) 141(10), 3564-9] vasodilation,bronchospasm, reflex or neuronal control of the viscera [Mantyh et al,PNAS (1988) 85, 3235-9] and, possibly by arresting or slowingβ-amyloid-mediated neurodegenerative changes [Yankner et al, Science(1990) 250, 279-82] in senile dementia of the Alzheimer type,Alzheimer's disease and Down's Syndrome.

Tachykinin antagonists may also be useful in the treatment of small cellcarcinomas, in particular small cell lung cancer (SCLC) [Langdon et al,Cancer Research (1992) 52, 4554-7].

Substance P may also play a role in demyelinating diseases such asmultiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod etal, poster C.I.N.P. XVIIth Congress, Jun. 28th-Jul. 2nd 1992], and indisorders of bladder function such as bladder detrusor hyper-reflexia(Lancet, May 16th 1992, 1239).

It has furthermore been suggested that tachykinins have utility in thefollowing disorders: depression, dysthymic disorders, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, vasospastic diseases such as angina and Reynauld's disease,fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, neuropathy, neuralgia, disorders related to immuneenhancement or suppression such as systemic lupus erythmatosus (Europeanpatent specification no. 0 436 334), ophthalmic disease such asconjuctivitis, vernal conjunctivitis, and the like, and cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis (European patent specification no. 0 394989).

European patent specification no. 0 577 394 (published Jan. 5, 1994)discloses morpholine and thiomorpholine tachykinin receptor antagonistsof the general formula ##STR2## wherein R^(1a) is a large variety ofsubstituents; R^(2a) and R^(3a) are inter alia hydrogen;

R^(4a) is inter alia ##STR3## R^(5a) is inter alia optionallysubstituted phenyl; R^(6a), R^(7a) and R^(8a) are a variety ofsubstituents;

X^(a) is O, S, SO or SO₂ ;

Y^(a) is inter alia O; and

Z^(a) is hydrogen or C₁₋₄ alkyl.

International Patent Specification no. WO 95/06645 discloses piperidinederivatives as tachykinin receptor antagonists of the general formula##STR4## wherein R is hydrogen or C₁₋₄ alkoxy; R^(1b) is phenyl,optionally substituted by --(CH₂)₁₋₂ CONR^(3b) R^(4b) or S(O)₁₋₂ R^(3b)or a 5-or 6-membered aromatic heterocycle containing 1, 2, 3 or 4heteroatoms selected from O, N, or S, optionally substituted by C₁₋₄alkyl, CF₃, CN or --(CH₂)₁₋₂ CONR^(3b) R^(4b) ;

R^(2b) is hydrogen or halogen;

R^(3b) and R^(4b) are hydrogen or C₁₋₄ alkyl; and

x is zero or 1.

We have now found a further class of non-peptides which are potentantagonists of tachykinins, especially of substance P.

The present invention provides compounds of the formula (I): ##STR5##wherein

R¹ is phenyl or a 5- or 6-membered aromatic heterocyclic groupcontaining 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen andsulphur, which aryl or heteroaryl group is optionally substituted by oneor two substituents selected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃,OCF₃, NO₂, CN, SR^(a), SOR^(a), SO₂ R^(a), COR^(a), CO₂ R^(a), (CH₂)_(n)CONR^(a) R^(b), (CH₂)_(n) NR^(a) R^(b) or (CH₂)_(n) NR^(a) COR^(b),where R^(a) and R^(b) are independently hydrogen or C₁₋₄ alkyl and n iszero, 1 or 2;

R² is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, OCF₃, NO₂, CN,SR^(a), SOR^(a), SO₂ R^(a), CO₂ R^(a), CONR^(a) R^(b), C₂₋₆ alkenyl,C₂₋₆ alkynyl or C₁₋₄ alkyl substituted by C₁₋₄ alkoxy, where R^(a) andR^(b) each independently represent hydrogen or C₁₋₄ alkyl;

R⁴ is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, NO₂, CN, SR^(a),SOR^(a), SO₂ R^(a), CO₂ R^(a), CONR^(a) R^(b), C₂₋₆ alkenyl, C₂₋₆alkynyl or C₁₋₄ alkyl substituted by C₁₋₄ alkoxy, where R^(a) and R^(b)each independently represent hydrogen or C₁₋₄ alkyl;

R⁵ is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy substituted by C₁₋₄alkoxy or CF₃ ;

R⁶ is a 5-membered or 6-membered heterocyclic ring containing 2 or 3nitrogen atoms optionally substituted by ═O, ═S or a C₁₋₄ alkyl group,and optionally substituted by a group of the formula ZNR⁷ R⁸ where

Z is C₁₋₆ alkylene or C₃₋₆ cycloalkylene;

R⁷ is hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or C₃₋₇ cycloalkylC₁₋₄alkyl, or C₂₋₄ alkyl substituted by C₁₋₄ alkoxy or hydroxyl;

R⁸ is hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl or C₃₋₇ cycloalkylC₁₋₄alkyl, or C₂₋₄ alkyl substituted by one or two substituents selectedfrom C₁₋₄ alkoxy, hydroxyl or a 4, 5 or 6 membered heteroaliphatic ringcontaining one or two heteroatoms selected from N, O and S;

or R⁷, R⁸ and the nitrogen atom to which they are attached form aheteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by oneor two groups selected from hydroxy or C₁₋₄ alkyl optionally substitutedby a C₁₋₄ alkoxy or hydroxyl group, and optionally containing a doublebond, which ring may optionally contain an oxygen or sulphur ring atom,a group S(O) or S(O)₂ or a second nitrogen atom which will be part of aNH or NR^(c) moiety where R^(c) is C₁₋₄ alkyl optionally substituted byhydroxy or C₁₋₄ alkoxy;

or R⁷, R⁸ and the nitrogen atom to which they are attached form anon-aromatic azabicyclic ring system of 6 to 12 ring atoms;

or Z, R⁷ and the nitrogen atom to which they are attached form aheteroaliphatic ring of 4 to 7 ring atoms which may optionally containan oxygen ring atom;

R^(9a) and R^(9b) are each independently hydrogen or C₁₋₄ alkyl, orR^(9a) and R^(9b) are joined so, together with the carbon atoms to whichthey are attached, there is formed a C₅₋₇ ring;

the dotted line is an optional double bond;

A is --O-- or --CH₂ --;

Q¹ is oxygen, sulphur or --NH--;

Q² is --N═, --NH--, --CH═ or --CH₂ --;

X is an alkylene chain of 1 to 4 carbon atoms optionally substituted byoxo;

Y is hydrogen or a C₁₋₄ alkyl group optionally substituted by a hydroxylgroup; and

m is zero or 1; and pharmaceutically acceptable salts and prodrugsthereof

According to an alternative aspect of the present invention, Y is a C₁₋₄alkyl group optionally substituted by a hydroxyl group.

Certain particularly apt compounds of the present invention includethose wherein R¹ is a group selected from phenyl, pyrrole, furan,thiene, pyridine, pyrazole, imidazole, oxazole, isoxazole, thiazole,isothiazole, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole,thiadiazole, triazine, and tetrazole, each of which aryl or heteroarylgroups being optionally substituted as previously defined.

Preferred compounds of the present invention are those wherein R¹ is agroup selected from phenyl, furan, pyridine, pyrazole, imidazole,oxazole, isoxazole, pyrazine, pyrimidine, thiazole, 1,2,3-triazole,1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and tetrazole, eachof which aryl or heteroaryl groups being optionally substituted aspreviously defined.

Particularly preferred compounds of the present invention are thosewherein R¹ is a group selected from phenyl, furan, pyridine, pyrimidine,1,2,3-triazole, 1,2,4-triazole and tetrazole.

An especially preferred class of compound of formula (I) is that whereinR¹ is the group ##STR6## where R¹⁰ is halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,CF₃, OCF₃, NO₂, CN, SR^(a), SOR^(a), SO₂ R^(a), COR^(a), CO₂ R^(a),(CH₂)_(n) CONR^(a) R^(b), (CH₂)_(n) NR^(a) R^(b) or (CH₂)_(n) NR^(a)COR^(b), where R^(a) and R^(b) are hydrogen or C₁₋₄ alkyl, and n iszero, 1 or 2.

Another especially preferred class of compound of formula (I) is thatwherein R¹ is the group ##STR7## wherein R¹⁰ is as previously defined.

R¹⁰ is preferably hydrogen, C₁₋₄ alkyl, especially methyl, CF₃,(CH₂)_(n) CONR^(a) R^(b), SOR^(a) or SO₂ R^(a) where R^(a), R^(b) and nare as previously defined.

Most aptly R² is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, CF₃ orOCF₃.

Preferably R² is hydrogen or methoxy, especially hydrogen.

The group R² may be attached to any available position on the 6/5-fusedring. Most preferably R² is attached to the carbon atom in between thegroup R¹ --(CH₂)_(m) -- and the remainder of the molecule.

Most aptly R⁴ is hydrogen.

Most aptly R⁵ is hydrogen, fluorine, chlorine or CF₃.

Preferably R⁴ is hydrogen and R⁵ is hydrogen or 4-fluoro.

Most aptly R^(9a) and R^(9b) are each independently hydrogen or methyl.

Preferably R^(9a) is hydrogen. Preferably R^(9b) is hydrogen. Mostpreferably R^(9a) and R^(9b) are both hydrogen.

Preferably m is zero.

Preferably A is --O--.

Preferably Q¹ is an oxygen atom.

Preferably Q² is --CH═ or --CH₂ --.

Preferably the dotted line represents a double bond.

Regarding the definition of R¹ above, where R¹ represents 5- or6-membered aromatic heterocyclic group, such a group may be attached tothe remainder of the molecule via any available carbon or nitrogen atom.

The aryl or heteroaryl group represented by R¹ may be substituted by oneor two substituents at any available position on the aryl or heteroarylgroup.

When R¹ is a phenyl group, a suitable susbtituent is SO₂ CH₃.

When R¹ is an aromatic heterocyclic group, preferred substituentsinclude methyl, CN, CF₃ or CON(CH₃)₂. For instance, when R¹ is apyridine group, suitable substituents include methyl, CN and CON(CH₃)₂ ;when R¹ is a pyrazole, imidazole, isoxazole or triazole group, suitablesubstituents include one or two methyl groups; and when R¹ is tetrazole,suitable substituents include methyl or CF₃.

From the foregoing it will be appreciated that a particularly aptsub-group of compounds of this invention are those of the formula (Ia)and pharmaceutically acceptable salts and prodrugs thereof: ##STR8##wherein A, X, Y, R¹, R², R⁶, Q¹, Q² and the dotted line are as definedin relation to formula (I) and A¹ is fluorine or hydrogen.

According to a second or further aspect of the present invention, apreferred class of compound of formula (I) or (Ia) is that wherein Yrepresents a C₁₋₄ alkyl group; or a pharmaceutically acceptable salt orprodrug thereof.

According to a further or alternative aspect of the present invention,another preferred class of compound of formula (I) or (Ia) is thatwherein R⁶ is substituted at least by a group of the formula ZNR⁷ R⁸ asdefined above; or a pharmaceutically acceptable salt or prodrug thereof

When the group Y in compounds of the formulae (I) or (Ia) is a C₁₋₄alkyl group susbtituted by a hydroxy group,a preferred group is the CH₂OH group.

Another preferred group Y for compounds of the formulae (I) or (Ia) isthe CH₃ group.

Particularly apt values for X for compounds of the formulae (I) or (Ia)include CH₂, CH(CH₃) and CH₂ CH₂ of which the CH₂ group is preferred.

Favourably R⁶ is a 5-membered ring.

In particular, R⁶ may, represent a heterocyclic ring selected from:##STR9##

Particularly preferred heterocyclic rings represented by R⁶ are selectedfrom: ##STR10##

Most especially, R⁶ may represent a heterocyclic ring selected from:##STR11##

A particularly preferred heterocyclic ring represented by R⁶ is:##STR12##

One favored group of compounds of this invention are of the formula (Ib)and pharmaceutically acceptable salts thereof. ##STR13## wherein A¹ isas defined in relation to formula (Ia), wherein A, Z, R¹, R², R⁷, R⁸,Q¹, Q², the dotted line and m are as defined in relation to formula (I)and wherein Y¹ is hydrogen or methyl.

A further favored group of compounds of the present invention are of theformula (Ic) and pharmaceutically acceptable salts thereof: ##STR14##wherein A¹ is as defined in relation to formula (Ia);Y¹ is hydrogen ormethyl; and R¹, R⁷, R⁸ and Z are as defined in relation to formula (I).

With respect to compounds of the formulae (I), (Ia), (Ib), and (Ic), Zmay be a linear, branched or cyclic group. Favorably Z contains 1 to 4carbon atoms and most favorably 1 or 2 carbon atoms. A particularlyfavorable group Z is CH₂.

With respect to compounds of the formulae (I), (Ia), (Ib), and (Ic), R⁷may aptly be a C₁₋₄ alkyl group or a C₂₋₄ alkyl group substituted by ahydroxyl or C₁₋₂ alkoxy group, R⁸ may aptly be a C₁₋₄ alkyl group or aC₁₋₄ alkyl group substituted by a hydroxyl or C₁₋₂ alkoxy group, or R⁷and R⁸ may be linked so that, together with the nitrogen atom to whichthey are attached, they form an azetidinyl, pyrrolidinyl, piperidyl,morpholino, thiomorpholino, piperazino or piperazino group substitutedon the nitrogen atom by a C₁₋₄ alkyl group or a C₂₋₄ alkyl groupsubstituted by a hydroxy or C₁₋₂ alkoxy group.

Where the group NR⁷ R⁸ represents a heteroaliphatic ring of 4 to 7 ringatoms and said ring contains a double bond, a particularly preferredgroup is 3-pyrroline.

Where the group NR⁷ R⁸ represents a non-aromatic azabicyclic ringsystem, such a system may contain between 6 and 12, and preferablybetween 7 and 10, ring atoms. Suitable rings include5-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.2.1]heptyl,6-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl,6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl,6-azabicyclo[3.2.2]cdecyl, 7-azabicyclo[4.3.1]decyl,7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.

Where R⁸ represents a C₂₋₄ alkyl group substituted by a 5 or 6 memberedheteroaliphatic ring containing one or two heteroatoms selected from N,O and S, suitable rings include pyrrolidino, piperidino, piperazino,morpholino, or thiomorpholino. Particularly preferred are nitrogencontaining heteroaliphatic rings, especially pyrrolidino and morpholinorings.

Particularly suitable moieties ZNR⁷ R⁸ include those wherein Z is CH₂ orCH₂ CH₂ and NR⁷ R⁸ is amino, methylamino, dimethylamino, diethylamino,azetidinyl, pyrrolidino and morpholino.

Further preferred moieties represented by ZNR⁷ R⁸ are those wherein Z isCH₂ or CH₂ CH₂, R⁷ represents hydrogen, C₁₋₄ alkyl or C₃₋₆ cycloalkyland R⁸ is C₂₋₄ alkyl substituted by one or two substituents selectedfrom hydroxy, C₁₋₂ alkoxy, azetidinyl, pyrrolidino, piperidino,morpholino or thiomorpholino.

In particular, Z is preferably CH₂ and NR⁷ R⁸ is preferablydimethylamino, azetidinyl or pyrrolidino, especially dimethylamino.

As used herein, the term "alkyl" or "alkoxy" as a group or part of agroup means that the group is straight or branched. Examples of suitablealkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyland t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

The cycloalkyl groups referred to herein may represent, for example,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitablecycloalkylalkyl group may be, for example, cyclopropylmethyl.

As used herein, the terms "alkenyl" and "alkynyl" as a group or part ofa group means that the group is straight or branched. Examples ofsuitable alkenyl groups include vinyl and allyl. A suitable alkynylgroup is propargyl.

When used herein the term halogen means fluorine, chlorine, bromine andiodine. The most apt halogens are fluorine and chlorine of whichfluorine is preferred.

Specific compounds within the scope of this invention include:

[2S,3S]-1-[(5-(dimethylaminomethyl)-1H-[1,2,3]triazol-4-yl)methyl]-2-phenyl-3-[[5-(1-methyl-1H-1,2,3-triazol-5-yl)benzofuran-7-yl]methyloxy]piperidine;

[2S,3S]-1-[(5-(dimethylaminomethyl)-1H-[1,2,3]triazol-4-yl)methyl]-2-phenyl-3-[(5-(5-methyl-1H-tetrazol-1-yl)benzofuran-7-yl)methyloxy]piperidine;

and pharmaceutically acceptable salts or prodrugs thereof.

Further preferred compounds within the scope of the present inventionare described in the Examples described herein.

In a further aspect of the present invention, the compounds of formula(I) will preferably be prepared in the form of a pharmaceuticallyacceptable salt, especially an acid addition salt.

For use in medicine, the salts of the compounds of formula (I) will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of the compound according to the invention with a solution ofa pharmaceutically acceptable acid such as hydrochloric acid, fumaricacid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid,citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuricacid. Salts of amine groups may also comprise quaternary ammonium saltsin which the amino nitrogen atom carries a suitable organic group suchas an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include metal salts suchas alkali metal salts, e.g. sodium or potassium salts; and alkalineearth metal salts, e.g. calcium or magnesium salts.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the "parent drug" or "parent molecule")that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxylic, phosphoric or sulphate ester, or reductionor oxidation of a susceptible functionality.

Thus, for example, certain preferred prodrugs may not be antagonists oftachykinin, particularly substance P, activity to any significant extent(or not at all). Such compounds, however, are still advantageous intreating the various conditions described herein, especially where aninjectable formulation is preferred.

The advantages of a prodrug may lie in its physical properties, such asenhanced water solubility for parenteral administration compared withthe parent drug, or it may enhance absorption from the digestive tract,or it may enhance drug stability for long-term storage. Ideally aprodrug will improve the overall efficacy of a parent drug, for example,through the reduction of toxicity and unwanted effects of drugs bycontrolling their absorption, blood levels, metabolism, distribution andcellular uptake.

The present invention includes within its scope solvates of thecompounds of formula (I) and salts thereof, for example, hydrates.

The compounds according to the invention have at least three asymmetriccentres, and may accordingly exist both as enantiomers and asdiastereoisomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The preferred compounds of the formula (I), (Ia), (Ib) and (Ic), willhave the 2- and 3-substituent cis. The preferred stereochemistry at the2-position is either (R) when A is --O-- or (S) when A is --CH₂ --, forinstance, that possessed by the compound of Example 1 (i.e. 2-(S)). Thepreferred stereochemistry of the 3-position is that possessed by thecompound of Example 1 (i.e. 3-(S)). The preferred stereochemistry of thecarbon to which the group Y is either (R) when Y is C₁₋₄ alkyl (e.g.methyl) or (S) when Y is C₁₋₄ alkyl substituted by hydroxy (e.g. CH₂OH). Thus for example as shown in formula (Id) ##STR15##

The present invention further provides pharmaceutical compositionscomprising one or more compounds of formula (I) in association with apharmaceutically acceptable carrier.

Preferably the compositions according to the invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,solutions or suspensions, or suppositories, for oral, parenteral orrectal administration, or administration by inhalation or insufflation.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pils and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pils of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

Preferred compositions for administration by injection include thosecomprising a compound of formula (I), as the active ingredient, inassociation with a surface-active agent (or wetting agent or surfactant)or in the form of an emulsion (as a water-in-oil or oil-in-wateremulsion).

Suitable surface-active agents include anionic agents such as sodiumbis-(2-ethylhexyl)sulfosuccinate (docusate sodium), cationic agents,such as alkyltrimethylammonium bromides, (e.g. cetyltrimethylammoniumbromide (cetrimide)), and in particular, non-ionic agents, such aspolyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) and othersorbitans (e.g. Span™ 20, 40, 60, 80 or 85). Compositions with asurface-active agent will conveniently comprise between 0.05 and 5%surface-active agent, and preferably between 0.1 and 2.5%. It will beappreciated that other ingredients may be added, for example mannitol orother pharmaceutically acceptable vehicles, if necessary.

Suitable emulsions may be prepared using commercially available fatemulsions, such as Intralipid™, Liposyn™, lnfonutrol™, Lipofundin™ andLipiphysan™. The active ingredient may be either dissolved in apre-mixed emulsion composition or alternatively it may be dissolved inan oil (e.g. soybean oil, safflower oil, cottonseed oil, sesame oil,corn oil or almond oil) and an emulsion formed upon mising with aphospholipid (e.g. egg phospholipids, soybean phospholipids or soybeanlecithin) and water. It will be appreciated that other ingredients maybe added, for example glycerol or glucose, to adjust the tonicity of theemulsion. Suitable emulsions will typically contain up to 20% oil, forexample, between 5 and 20%. The fat emulsion will preferably comprisefat droplets between 0.1 and 1.0 μm, particularly 0.1 and 0.5 μm, andhave a pH in the range of 5.5 to 8.0.

Particularly preferred emulsion compositions are those prepared bymixing a compound of formula (I) with Intralipid™ or the componentsthereof (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The present invention father provides a process for the preparation of apharmaceutical composition comprising a compound of formula (I), whichprocess comprises bringing a compound of formula (I) into associationwith a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity.

Thus, for example, an excess of tachykinin, and in particular substanceP, activity is implicated in a variety of disorders of the centralnervous system. Such disorders include mood disorders, such asdepression or more particularly depressive disorders, for example,single episodic or recurrent major depressive disorders and dysthymicdisorders, or bipolar disorders, for example, bipolar I disorder,bipolar II disorder and cyclothymic disorder; anxiety disorders, such aspanic disorder with or without agoraphobia, agoraphobia without historyof panic disorder, specific phobias, for example, specific animalphobias, social phobias, obsessive-compulsive disorder, stress disordersincluding post-traumatic stress disorder and acute stress disorder, andgeneralised anxiety disorders; schizophrenia and other psychoticdisorders, for example, schizophreniform disorders, schizoaffectivedisorders, delusional disorders, brief psychotic disorders, sharedpsychotic disorders and psychotic disorders with delusions orhallucinations; delerium, dementia, and amnestic and other cognitive orneurodegenerative disorders, such as Alzheimer's disease, seniledementia, dementia of the Alzheimer's type, vascular dementia, and otherdementias, for example, due to HIV disease, head trauma, Parkinson'sdisease, Huntington's disease, Pick's disease, Creutzfeldt-Jakobdisease, or due to multiple aetiologies; Parkinson's disease and otherextra-pyramidal movement disorders such as medication-induced movementdisorders, for example, neuroleptic-induced parkinsonism, neurolepticmalignant syndrome, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia and medication-induced postural tremour; substance-relateddisorders arising from the use of alcohol, amphetamines (oramphetamine-like substances) caffeine, cannabis, cocaine, hallucinogens,inhalants and aerosol propellants, nicotine, opioids, phenylglycidinederivatives, sedatives, hypnotics, and anxiolytics, whichsubstance-related disorders include dependence and abuse, intoxication,withdrawal, intoxication delerium, withdrawal delerium, persistingdementia, psychotic disorders, mood disorders, anxiety disorders, sexualdysfunction and sleep disorders; epilepsy; Down's syndrome;demyelinating diseases such as MS and ALS and other neuropathologicaldisorders such as peripheral neuropathy, for example diabetic andchemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia and other neuralgias; andcerebral vascular disorders due to acute or chronic cerebrovasculardamage such as cerebral infarction, subarachnoid haemorrhage or cerebraloedema.

Tachykinin, and in particular substance P, activity is also involved innociception and pain. The compounds of the present invention willtherefore be of use in the prevention or treatment of diseases andconditions in which pain predominates, including soft tissue andperipheral damage, such as acute trauma, osteoarthritis, rheumatoidarthritis, musculo-skeletal pain, particularly after trauma, spinalpain, myofascial pain syndromes, headache, episiotomy pain, and burns;deep and visceral pain, such as heart pain, muscle pain, eye pain,orofacial pain, for example, odontalgia, abdominal pain, gynaecologicalpain, for example, dysmenorrhoea, and labour pain; pain associated withnerve and root damage, such as pain associated with peripheral nervedisorders, for example, nerve entrapment and brachial plexus avulsions,amputation, peripheral neuropathies, tic douloureux, atypical facialpain, nerve root damage, and arachnoiditis; pain associated withcarcinoma, often referred to as cancer pain; central nervous systempain, such as pain due to spinal cord or brain stem damage; low backpain; sciatica; ankylosing spondylitis, gout; and scar pain.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of respiratory diseases, particularly thoseassociated with excess mucus secretion, such as chronic obstructiveairways disease, bronchopneumonia, chronic bronchitis, cystic fibrosisand asthma, adult respiratory distress syndrome, and bronchospasm;inflammatory diseases such as inflammatory bowel disease, psoriasis,fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn;allergies such as eczema and rhinitis; hypersensitivity disorders suchas poison ivy; ophthalmic diseases such as conjunctivitis, vernalconjunctivitis, and the like; ophthalmic conditions associated with cellproliferation such as proliferative vitreoretinopathy; cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of neoplasms, including breast tumors,eneuroganglioblastomas and small cell carcinomas such as small cell lungcancer.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of gastrointestinal (GI) disorders, includinginflammatory disorders and diseases of the GI tract such as gastritis,gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disordersassociated with the neuronal control of viscera, ulcerative colitis,Crohn's disease, irritable bowel syndrome and emesis, including acute,delayed or anticipatory emesis such as emesis induced by chemotherapy,radiation, toxins, viral or bacterial infections, pregnancy, vestibulardisorders, for example, motion sickness, vertigo, dizziness andMeniere's disease, surgery, migraine, variations in intercranialpressure, gastro-oesophageal reflux disease, acid indigestion, overindulgence in food or drink, acid stomach, waterbrash or regurgitation,heartburn, for example, episodic, nocturnal or meal-induced heartburn,and dyspepsia.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of a variety of other conditions including stressrelated somatic disorders; reflex sympathetic dystrophy such asshoulder/hand syndrome; adverse immunological reactions such asrejection of transplanted tissues and disorders related to immuneenhancement or suppression such as systemic lupus erythematosus; plasmaextravasation resulting from cytokine chemotherapy, disorders of bladderfunction such as cystitis, bladder detrusor hyper-reflexia andincontinence; fibrosing and collagen diseases such as scleroderma andeosinophilic fascioliasis; disorders of blood flow caused byvasodilation and vasospastic diseases such as angina, vascular headache,migraine and Reynaud's disease; and pain or nociception attributable toor associated with any of the foregoing conditions, especially thetransmission of pain in migrame.

The compounds of formula (I) are also of value in the treatment of acombination of the above conditions, in particular in the treatment ofcombined post-operative pain and post-operative nausea and vomiting.

The compounds of formula (I) are particularly useful in the treatment ofemesis, including acute, delayed or anticipatory emesis, such as emesisinduced by chemotherapy, radiation, toxins, pregnancy, vestibulardisorders, motion, surgery, migraine, and variations in intercranialpressure. Most especially, the compounds of formula (I) are of use inthe treatment of emesis induced by antineoplastic (cytotoxic) agentsincluding those routinely used in cancer chemotherapy.

Examples of such chemotherapeutic agents include alkylating agents, forexample, nitrogen mustards, ethyleneimine compounds, alkyl sulphonatesand other compounds with an alkylating action such as nitrosoureas,cisplatin and dacarbazine; antimetabolites, for example, folic acid,purine or pyrimidine antagonists; mitotic inhibitors, for example, vincaalkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.

Particular examples of chemotherapeutic agents are described, forinstance, by D. J. Stewart in Nausea and Vomiting: Recent Research andClinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton,Fla., USA (1991) pages 177-203, especially page 188. Commonly usedchemotherapeutic agents include cisplatin, dacarbazine (DTIC),dactinomycin, mechlorethamine (nitrogen mustard), streptozocin,cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin(adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine,etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine,bleomycin and chlorambucil [R. J. Gralla et al in Cancer TreatmentReports (1984) 68(1), 163-172].

The compounds of formula (I) are also of use in the treatment of emesisinduced by radiation including radiation therapy such as in thetreatment of cancer, or radiation sickness; and in the treatment ofpost-operative nausea and vomiting.

It will be appreciated that the compounds of formula (I) may bepresented together with another therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use for the reliefof emesis. Such combined preparations may be, for example, in the formof a twin pack.

A further aspect of the present invention comprises the compounds offormula (I) in combination with a 5-HT₃ antagonist, such as ondansetron,granisetron or tropisetron, or other anti-emetic medicaments, forexample, a dopamine antagonist such as metoclopramide. Additionally, acompound of formula (I) may be administered in combination with ananti-inflammatory corticosteroid, such as dexamethasone. Furthermore, acompound of formula (I) may be administered in combination with achemotherapeutic agent such as an alkylating agent, antimetabolite,mitotic inhibitor or cytotoxic antibiotic, as described above. Ingeneral, the currently available dosage forms of the known therapeuticagents for use in such combinations will be suitable.

When tested in the ferret model of cisplatin-induced emesis described byF. D. Tattersall et al, in Eur. J. pharmacol., (1993) 250, R5-R6, thecompounds of the present invention were found to attenuate the retchingand vomiting induced by cisplatin.

The compounds of formula (I) are also particularly useful in thetreatment of pain or nociception and/or inflammation and disordersassociated therewith such as, for example, neuropathy, such as diabeticand chemotherapy-induced neuropathy, postherpetic and other neuralgias,asthma, osteroarthritis, rheumatoid arthritis and headache, includingmigraine, acute or chronic tension headache, cluster headache,temporomandibular pain, and maxillary sinus pain.

The present invention further provides a compound of formula (I) for usein therapy.

According to a further or alternative aspect, the present inventionprovides a compound of formula (I) for use in the manufacture of amedicament for the treatment of physiological disorders associated withan excess of tachykinins, especially substance P.

The present invention also provides a method for the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of formula (I) or a composition comprising acompound of formula (I).

For the treatment of certain conditions it may be desirable to employ acompound according to the present invention in conjunction with anotherpharmacologically active agent. For example, for the treatment ofrespiratory diseases such as asthma, a compound of formula (I) may beused in conjunction with a bronchodilator, such as a β₂ -adrenergicreceptor agonist or tachykinin antagonist which acts at NK-2 receptors.The compound of formula (I) and the bronchodilator may be administeredto a patient simultaneously, sequentially or in combination.

Likewise, a compound of the present invention may be employed with aleukotriene antagonists, such as a leukotriene D₄ antagonist such as acompound selected from those disclosed in European patent specificationnos. 0 480 717 and 0 604 114 and in U.S. Pat. Nos. 4,859,692 and5,270,324. This combination is particularly useful in the treatment ofrespiratory diseases such as asthma, chronic bronchitis and cough.

The present invention accordingly provides a method for the treatment ofa respiratory disease, such as asthma, which method comprisesadministration to a patient in need thereof of an effective amount of acompound of formula (I) and an effective amount of a bronchodilator.

The present invention also provides a composition comprising a compoundof formula (I), a bronchodilator, and a pharmaceutically acceptablecarrier.

It will be appreciated that for the treatment or prevention of migraine,a compound of the present invention may be used in conjunction withother anti-migraine agents, such as ergotamines or 5-HT₁ agonists,especially sumatriptan.

Likewise, for the treatment of behavioural hyperalgesia, a compound ofthe present invention may be used in conjunction with an antagonist ofN-methyl D-aspartate HNMDA), such as dizocilpine.

For the treatment or prevention of inflammatory conditions in the lowerurinary tract, especially cystitis, a compound of the present inventionmay be used in conjunction with an anti-inflammatory agent such as abradykinin receptor antagonist.

The present invention also provides a composition comprising a compoundof formula (I), a bronchodilator, and a pharmaceutically acceptablecarier.

It will be appreciated that for the treatment or prevention of pain ornociception, a compound of the present invention may be used inconjunction with other analgesics, such as acetaminophen (paracetamol),aspirin and other NSAIDs and, in particular, opioid analgesics,especially morphine. Specific anti-inflammatory agents includediclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam andsulindac. Suitable opioid analgesics of use in conjunction with acompound of the present invention include morphine, codeine,dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone,levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol,fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxypheneand pentazocine; or a pharmaceutically acceptable salt thereof.Preferred salts of these opioid analgesics include morphine sulphate,morphine hydrochloride, morphine tartrate, codeine phosphate, codeinesulphate, dihydrocodeine bitartrate, diacetylmorphine hydrochloride,hydrocodone bitartrate, hydromorphone hydrochloride, levorphanoltartrate, oxymorphone hydrochloride, alfentanil hydrochloride,buprenorphine hydrochloride, butorphanol tartrate, fentanyl citrate,meperidine hydrochloride, methadone hydrochloride, nalbuphinehydrochloride, propoxyphene hydrochloride, propoxyphene napsylate(2-naphthalenesulphonic acid (1:1) monohydrate), and pentazocinehydrochloride.

Therefore, in a further aspect of the present invention, there isprovided a pharmaceutical composition comprising a compound of thepresent invention and an analgesic, together with at least onepharmaceutically acceptable carrier or excipient.

In a further or alternative aspect of the present invention, there isprovided a product comprising a compound of the present invention and ananalgesic as a combined preparation for simultaneous, separate orsequential use in the treatment or prevention of pain or nociception.

The excellent pharmacological profile of the compounds of the presentinvention offers the opportunity for their use in therapy at low dosesthereby minimising the risk of unwanted side effects.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg per day.

For example, in the treatment of conditions involving theneurotransmission of pain sensations, a suitable dosage level is about0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day,and especially about 0.005 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

In the treatment of emesis using an injectable formulation, a suitabledosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005to 5 mg/kg per day, and especially 0.01 to 1 mg/kg per day. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

It will be appreciated that the amount of a compound of formula (I)required for use in any treatment will vary not only with the particularcompounds or composition selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

According to a general process (A), the compounds according to theinvention may be prepared from compounds of formula (II) ##STR16##wherein R¹, R², R³, R⁴, R⁵, R^(9a), R^(9b), A, Y, Q¹, Q², the dottedline and m are as defined in relation to formula (I) by reaction with acompound of formula (III):

    X.sup.1 --X--R.sup.6a                                      (III)

where X is as defined in relation to formula (I), R^(6a) is a group ofthe formula R⁶ as defined in relation to formula (I) or a precursortherefor and X¹ is a leaving group such as bromine or chlorine; and, ifR^(6a) is a precursor group, converting it to a group R⁶ (in whichprocess any reactive group may be protected and thereafter deprotectedif desired).

This reaction may be performed in conventional manner, for example in anorganic solvent such as dimethylformamide in the presence of an acidacceptor such as potassium carbonate.

According to another process (B), compounds of formula (I) wherein R⁶represents 1,2,3-triazol-4-yl substituted by CH₂ NR⁷ R⁸, and X is --CH₂--, may be prepared by reaction of a compound of formula (IV) ##STR17##with an azide, for example, sodium azide in a suitable solvent such asdimethylsulphoxide at a temperature of between 40° C. and 100° C.,followed by reduction of the carbonyl group adjacent to --NR⁷ R⁸ using asuitable reducing agent such as lithium aluminum hydride at at atemperature between -10° C. and room temperature, conveniently at roomtemperature.

Alternatively, according to a process (C), compounds of formula (I)wherein R⁶ represents 1,2,3-triazol-4-yl substituted by CH2NR⁷ R⁸, and Xis --CH₂ --, may be prepared by reaction of a compound of formula (V)##STR18## with an amine of formula NHR⁷ R⁸, in a suitable solvent suchas an ether, for example, dioxan, at elevated temperature, for example,between 50° C. and 100° C., in a sealed tube, or the like. This reactionis based upon that described in Chemische Berichte (1989) 122, p. 1963.

According to another process, (D), compounds of formula (I) wherein R⁶represents substituted or unsubstituted 1,3,5-triazine may be preparedby reaction of intermediates of formula (VI): ##STR19## with substitutedor unsubstituted 1,3,5-triazine.

The reaction is conveniently effected in a suitable organic solvent,such as acetonitrile, at elevated temperature, such as 80-90° C.,preferably about 82° C.

According to a further process, (E), compounds of formula (I) wherein R⁶represents substituted or unsubstituted 1,2,4-triazine may be preparedby reaction of an intermediate of formula (VII) with a dicarbonylcompound of formula (VIII): ##STR20## wherein R³⁵ represents H or asuitable substituent such as ZNR⁷ R⁸.

The reaction is conveniently effected in a suitable organic solvent,such as an ether, e.g. tetrahydrofuran, conveniently at ambienttemperature.

According to a further process (F), compounds of formula (I) wherein R⁶represents a substituted 1,2,4-triazolyl group may be prepared byreaction of an intermediate of formula (II) with a compound of formula(IX) ##STR21## wherein X is as defined in relation to formula (I), Halis a halogen atom, for example, bromine, chlorine or iodine and R¹⁸ isH, CONH₂ or OCH₃ (which is converted to an oxo substituent under thereaction conditions), in the presence of a base, followed wherenecessary by conversion to a compound of formula (I), for example, byreduction of the CONH₂ group to CH₂ NH₂.

Suitable bases of use in the reaction include alkali metal carbonatessuch as, for example, potassium carbonate. The reaction is convenientlyeffected in an anhydrous organic solvent such as, for example, anhydrousdimethylformamide, preferably at elevated temperature, such as about140° C.

A suitable reducing agent for the group CONH₂ is lithium aluminiumhydride, used at between -10° C. and room temperature.

According to another process, (G), compounds of formula (I) wherein R⁶represents thioxotriazolyl may be prepared from intermediates of formula(X) ##STR22## by reaction with a compound of formula HNCS, in thepresence of a base.

Suitable bases of use in the reaction include organic bases such as, forexample, 1,8-diazabicyclo[5.4.0]undec-7-ene DBU). The reaction isconveniently effected in a suitable organic solvent, such as alcohol,e.g. butanol.

According to a further alternative general process (H), compounds offormula (I) wherein the heterocycle R⁶ is substituted by ZNR⁷ R⁸, may beprepared from an intermediate of formula (II) as defined above with oneof the compounds of formula (XI): ##STR23## wherein each LG, which maybe the same or different, is a leaving group, such as an alkyl- orarylsulphonyloxy group (e.g. mesylate or tosylate) or, in particular, ahalogen atom, (e.g. bromine, chlorine or iodine) and X and Z are asdefined in formula (I), followed by reaction of the resultant compoundwith an amine NHR⁷ R⁸ to complete the ZNR⁷ R⁸ moiety.

This reaction is conveniently effected in an organic solvent such asdimethylformamide in the presence of an acid acceptor such as potassiumcarbonate.

It will be appreciated that, where necessary, reactive groups may beprotected, thus for example, the NH groups of an imidazolinone offormula (XIa) may be protected by any suitable amine protecting groupsuch as an acetyl group.

According to another general process (J), compounds of formula (I) maybe prepared by reaction of intermediates of formula (XII) ##STR24##wherein LG is a suitable leaving group such as a halogen atom, e.g.bromine or iodine, or --OSO₂ CF₃, with a compound of formula (XIII)

    R.sup.1 --(CH.sub.2).sub.m --R.sup.40                      (XIII)

wherein R⁴⁰ is B(OH)₂, Sn(alkyl)₃, for example, Sn(methyl)₃ orSn(n-butyl)₃. Where R⁴⁰ is B(OH)₂, the reaction is conveniently effectedin the presence of a palladium (0) catalyst such astetrakis(triphenylphosphine)palladium (0), in a siutable solvent such asan ether, for example, dimethoxyethane, at an elevated temperature.Where R⁴⁰ is Sn(alkyl)₃, the reaction is conveniently effected in thepresnce of a palladium (II) catalyst such as bis(triphenylphosphine)palladium (II) chloride, in a suitable solvent such as an aromatichydrocarbon, for example, toluene, at an elevated temperature.

According to a preferred process (K) compounds of formula (I) wherein R¹is a tetrazol-1-yl group and m is zero, may be prepared by the reactionof intermediates of formula (XIV) ##STR25## with ammonium chloride andsodium azide at elevated temperature, conveniently in a solvent such asdimethylformamide.

Further details of suitable procedures will be found in the accompanyingExamples.

Compounds of formula (I) may also be prepared from other compounds offormula (I) using suitable interconversion procedures. For example,compounds of formula (I) wherein X represents C₁₋₄ alkyl may be preparedfrom compounds of formula (I) wherein X represents C₁₋₄ alkylsubstituted by oxo by reduction, for example, using borane or lithiumaluininium hydride. Suitable interconversion procedures will be readilyapparent to those skilled in the art.

Intermediates of formula (IV) may be prepared from intermediates offormula (II) by reaction with an acetylene compound of formulaHC.tbd.C--CH₂ --Hal in the presence of a base such as potassiumcarbonate in a suitable solvent such as dimethylformamide, convenientlyat room temperature, followed by reaction of the resultant acetyleneintermediate with an amide of formula Hal--CO--NR⁷ R⁸ in the presence ofsuitable catalysts including bis(triphenylphosphine) palladium(II)chloride, copper(I) iodide and triphenylphosphine in a suitable solventsuch as triethylamine, preferably at reflux.

Intermediates of formula (V) may be prepared from a compound of formula(XV) ##STR26## wherein Hal is a halogen atom, for example, chlorine,bromine or iodine, especially chlorine, by reaction with an azide, forexample, sodium azide in a suitable solvent such as dimethylsulphoxideat or below room temperature.

Compounds of formula (XV) may be prepared by a dropwise addition of anintermediate of formula (II) to a dihaloacetylene of formula Hal--CH₂--C.tbd.C--CH₂ --Hal where each Hal is independently chlorine, bromineor iodine, especially chlorine. The reaction is conveniently effected ina suitable solvent such as dimethylformamide in the presence of a basesuch as potassium carbonate.

Intermediates of formula (VI) may be prepared from intermediates offormula (II) by reaction with a compound of formula Hal--X--C(NH)NH₂,where Hal and X are as previously defined.

Intermediates of formula (VID may be prepared from intermediates offormula (II) by reaction with a compound of formulaHal--X--C(NH)NHNH--Boc, wherein Hal and X are as previously defined andBoc stands for t-butoxycarbonyl, followed by deprotection under acidicconditions.

Compounds of formula (VIII) are commercially available or may beprepared from commercially available compounds by known methods.

Compounds of formula (IX) may be prepared as described in J. Med. Chem.,(1984) 27, 849.

Intermediates of formula (X) may be prepared from the correspondingester by treatment with hydrazine. The reaction is conveniently effectedin a suitable organic solvent, such as an alcohol, for example, ethanol,at elevated temperature.

For compounds wherein R⁶ is a heterocycle substituted by a ZNR⁷ R⁸ groupwhere Z is CH₂, certain favored compounds of formula (I) may be preparedfrom a corresponding compound with a hydrogen atom in place of the ZNR⁷R⁸. Thus, for example a compound of the formula (I) wherein R⁶ is animidazolinone group carrying a CH₂ NR⁷ R⁸ moiety may be prepared from acorresponding compound lacking the CH₂ NR⁷ R⁸ moiety by reaction withformaldehyde and an amine NHR⁷ R⁸ under conventional Mannich reactionconditions, for example in methanol with heating. If desired apre-formed reagent such as R⁷ R⁸ N⁺ ═CH₂.I⁻ may be employed and atertiary amine such as triethylamine used as acid acceptor.

Alternatively a compound of formula (I) wherein R⁶ is an imidazolinonegroup lacking a CH₂ NR⁷ R⁸ may be reacted with paraformaldehyde and anamine for example a secondary amine such as pyrrolidine to give acompound wherein the imidazolinone ring is substituted by CH₂ NR⁷ R⁸where R⁷, R⁸ and the nitrogen atom to which they are attached form aheteroaliphatic ring of 4 to 7 ring atoms which may optionally containan oxygen ring atom or a second nitrogen atom which will be part of a NHor NR^(c) moiety, where R^(c) is as previously defined.

This reaction may be performed in a conventional manner, for instance,in a suitable solvent such as an alcohol, for example, methanol at anelevated temperature up to the boiling point of the solvent.

Compounds of formulae (XII and (XIV) may be prepared by reacting acompound of formula (XVI) or (XVII) ##STR27## respectively, with anysuitable reagent for completing the R⁶ --X-- moiety as described in anyone of processes (A) to (H).

Alternatively, compounds of formula (XII) may be preapred by reacting acompound of formula (XVIII) ##STR28## with a compound of formula (XIX)##STR29## where each LG independently represents a leaving group aspreviously defined.

Compounds of formula (XIII) and (XIX) may be prepared by conventionalmethodology, such as that described in International patentspecification No. WO 95/06645, published Mar. 9, 1995.

The preferred phosphate prodrugs of the compounds of the presentinvention are those wherein Y is a derivatized hydroxy substituted C₁₋₄alkyl group. Such preferred compounds may be prepared in a stepwisemanner from a compound of formula (I) wherein Y is, for example, --CH₂OH--.

Thus, the hydroxy compound is first treated withdibenzyloxydiethylaminophosphine in a suitable solvent such astetrahydrofuran, preferably in the presence of an acid catalyst such astetrazole. The resultant compound (Y═CH₂ OP(OCH₂ Ph)₂) is then oxidisedusing, for example, 4-methylmorpholine-N-oxide to give thedibenzyl-protected phosphate. Deprotection by catalytic hydrogenation ortransfer hydrogenation (palladium catalyst on carbon and ammoniumformate), in a suitable solvent such as methanol at reflux, yields thedesired phosphate prodrug which may be converted to any desired saltform by conventional methodology.

In an alternative two-step method, the hydroxy compound of formula (I)may be reacted with a suitable base such as sodium hydride intetrahydrofuran, and tetrabenzylpyrophosphate added to yield thedibenzyl-protected phosphate which may be deprotected as describedabove.

The compounds of the formula (II), wherein A is --CH₂ --, may beprepared by methods known in the art, for example as described inEuropean patent specification No. 0 528 495-A, published Feb. 24, 1993.

The compounds of the formula (II), wherein A is --O--, may be preparedas shown in the following Scheme in which Ar¹ represents the R¹, R², R³substituted phenyl group; Ar² represents the R⁴, R⁵ substituted phenylgroup and Ph represents phenyl: ##STR30##

L-Selectride is lithium tri-sec-butylborohydride.

The following references describe methods which may be applied by theskilled worker to the chemical synthesis set forth above once theskilled worker has read the disclosure herein:

(i) D. A. Evans et al., J. Am. Chem. Soc., (1990) 112, 4011.

(ii) I. Yanagisawa et al., J. Med. Chem., (1984) 27, 849.

(iii) R. Duschinsky et al., J. Am. Chem. Soc., (1948) 70, 657.

(iv) F. N. Tebbe et al., J. Am. Chem. Soc., (1978) 100, 3611.

(v) N. A. Petasis et al., J. Am. Chem. Soc., (1990) 112, 6532.

(vi) K. Takai et al., J. Org. Chem., (1987) 52, 4412.

The Examples disclosed herein produce predominently the preferredisomers. The unfavored isomers are also produced as minor components. Ifdesired they may be isolated and employed to prepare the variousstereoisomers in conventional manner, for example chromatography usingan appropriate column. However, the skilled worker will appreciate thatalthough the Examples have been optimized to the production of thepreferred isomers, variation in solvent, reagents, chromatography etccan be readily employed to yield the other isomers.

It will be appreciated that compounds of the formula (I) wherein R⁶contains an ═O or ═S substituent can exist in tautomeric forms. All suchtautomeric forms and mixtures thereof are included within thisinvention. Most aptly the ═O or ═S substituent in R⁶ is the ═Osubstituent.

Where they are not commercially available, the intermediates of formula(III) above may be prepared by the procedures described in theaccompanying Examples or by alternative procedures which will be readilyapparent to one skilled in the art.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The exemplified compounds of this invention were tested by the methodsset out at pages 36 to 39 of International Patent Specification No. WO93/01165. The compounds or, in the case of prodrugs, the parentcompounds, were found to be active with IC₅₀ at the NK₁ receptor of lessthan 100 nM on said test method.

The following non-limiting Examples further illustrate the presentinvention:

DESCRIPTION 1[2S,3S]-1-tert-Butoxycarbonyl-2-phenyl-3-[(5-bromobenzofuran-7-yl)methyloxy]piperidine

(i) 4-Bromo-1-[(2,2-dimethoxyethyl)oxy]-2-methylbenzene

Bromoacetaldehyde dimethylacetal (6.05 ml) was added to a stirredsolution of 4-bromo-2-methylphenol (10.0 g) and KOH (5.0 g) in dry DMSO(40 ml). The solution was warmed to 100° C. for 4 hours. After this timethe reaction mixture was cooled to room temperature and poured intowater (200 ml). The aqueous layer was extracted with ether (2×100 ml).The combined organic layers were separated, washed with 2N aqueous NaOH(2×50 ml), dried over MgSO₄, filtered, and the solvent removed underreduced pressure to afford a brown oil. Purification by MPLC (15% ethylacetate/n-hexane) afforded4-bromo-1-[(2,2-dimethoxyethyl)oxy]-2-methylbenzene as a colourless oil(6.24 g). ¹ H NMR (360 MHz,CDCl₃)δ2.21 (3H, s), 3.46 (6H,s), 3.98 (2H,d, J=3.6 Hz), 4.69 (1H, t, J=3.6 Hz), 6.56 (1H, d, J=7.2 Hz), 7.26 (1H,d, J=7.2 Hz), 7.39 (1H, s).

(ii) 5-Bromo-7-methyl-benzofuran

Polyphosphoric acid (2.0 g) was added to a solution of4-bromo-1-[(2,2-dimethyloxyethyl)oxy]-2-methylbenzene (6.24 g) intoluene (100 ml) and the resulting mixture was warmed to reflux for 4hours. The reaction mixture was cooled to room temperature and thesupernatant organic layer decanted off. The black residue was basifiedwith 2N aqueous Na₂ CO₃ and extracted with ethyl acetate (100 ml). Theorganic layers were combined, washed with brine (2×100 ml), dried overMgSO₄, ifitered, and the solvent removed under reduced pressure.Purification by MPLC (2% ethyl acetatein-hexane) gave5-bromo-7-methyl-benzofaran as a colourless oil (2.77 g). ¹ H NMR (360MHz,CDCl₃)δ2.48 (3H, s), 6.68 (1H, d, J=3.6 Hz), 7.13 (1H, s), 7.53 (1H,s), 7.60 (1H, d, J=3.6 Hz).

iii) 5-Bromo-7-bromomethyl Benzofuran

N-Bromosuccinimide (10.0 g) and di-benzoylperoxide (500 mg) were addedin five equal portions to a solution of 5-bromo-7-methylbenzofuran (9.7g) stirring at reflux in CCl₄ (100 ml), whilst being irradiated with an850 W lamp. After the final addition, the reaction was stirred at refluxfor a further 2 hours, then cooled to room temperature. The solution wasfiltered and the filtrate washed with 2N NaOH--H₂ O (40 ml), brine (40ml), dried over MgSO₄, filtered and the solvent removed under reducedpressure. Purification by MPLC (1% ethyl acetateln-hexane) gave5-bromo-7-bromomethyl benzofuran as a dlear oil (4.2 g). ¹ H NMR (360MHz,CDCl₃)δ4.86 (2H, s), 6.69 (1H, d, J=3.0 Hz), 7.54 (1H, s), 7.62 (1H,s), 7.86 (1H, d, J=3.0 Hz).

(iv)[2S,3S]-1-tert-Butoxycarbonyl-2-phenyl-3-[(5-bromobenzofuran-7-yl)methyloxy]piperidine

Potassium bis(trimethylsilyl)amide (300 mg) was added to a stirredsolution of [2S,3S]-N-tert-butoxycarbonyl-2-phenylpiperidine-3-ol (160mg) in dry 1,2-dimethoxyethane (3.0 ml) under a dry nitrogen atmosphere.After 30 minutes 5-bromo-7-bromomethylbenzofuran (290 mg) was added, andthe reaction stirred for 18 hours at room temperature. The resultingmixture was then diluted with water (50 ml), and extracted into ethylacetate (2×50 ml). The organic layers were separated and washed withbrine (20 ml), dried over MgSO₄, filtered and the solvent removed underreduced pressure. Purification by MPLC (20% ethyl acetate/n-hexane),afforded[2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[(5-bromobenzofuran-7-yl)methyloxy]piperidineas a yellow gum (136 mg). ¹ H NMR (360 MHz,CDCl₃)δ1.43 (9H, s), 1.65(2H, m), 1.92 (2H, m), 2.70 (1H, t d, J=7.2, 3.0 Hz), 3.74 (2H,m), 4.90(2H, d, J=5.0 Hz), 5.74 (1H, br s), 6.71 (1H, d, J=1.0 Hz), 7.30-7.42(4H, m), 7.58 (3H, m), 7.75 (1H, d, J=1.0 Hz); MS m/z CI⁺ 487 (M+H⁺).

DESCRIPTION 2 1-Methyl-5-tributylstannanyl-1H-[1,2,3]triazole

A solution of 1-methyl-1H-[1,2,3]triazole (350 mg) in drytetrahydrofuran (5.0 ml) was added dropwise under nitrogen to a stirred,cooled (-78° C.) solution of n-butyl lithium (2.81 ml of 1.6M solutionin hexanes) in dry tetrahydrofuran (10 ml). After 1 hourtributylchlorostannane (1.46 g) was added. The reaction was maintainedat -78° C. for 30 min. and then allowed to warm to room temperature over2 hours. The reaction mixture was diluted with brine (10 ml) andextracted into ethyl acetate (50 ml). The organic layer was separated,washed with brine (50 ml), dried over MgSO₄, filtered and the solventremoved under reduced pressure. The residue was purified by flash columnchromatography (20% ethyl acetate/n-hexane), to give1-methyl-5-tributylstannanyl-1H-[1,2,3]triazole as a yellow oil (1.03g). ¹ H NMR (360 MHz,CDCl₃)δ0.87 (9H, m), 1.15 (6H, m), 1.28 (6H, m),1.36 (6H, m), 4.02 (3H, s), 7.60 (1H, s); MS m/z CI⁺ 372 (M+H⁺).

DESCRIPTION 3[2S,3S]-2-Phenyl-3-{[5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl]methyloxy}piperidinehydrochloride

(i)[2S,3S]-1-tert-Butoxycarbonyl-2-phenyl-3{[5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl]-methyloxy}piperidine

Bis(triphenylphosphine)palladium dichloride (5.0 mg) was added to adegassed solution of[2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[(5-bromobenzofuran-7-yl)methyloxy]piperidine(111 mg), and 1-methyl-5-tributylstannanyl-1H-[1,2,3]triazole (165 mg)in dry toluene (5.0 ml) under a dry nitrogen atmosphere. The resultingsolution was warmed to reflux for 18 hours. After this time the reactionwas cooled to room temperature and the solvent removed under reducedpressure. The residue was partitioned between aqueous NaHCO₃ solution(10 ml, sat) and ethyl acetate. The organic layer was washed with brine(10 ml), dried over MgSO₄, filtered and the solvent removed underpressure. Purification by MPLC (1:1 ethyl acetate/n-hexane) afforded[2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-{[5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl]methyloxy}piperidineas a yellow foam (51 mg). ¹ H NMR (360 MHz,CDCl₃)δ1.45 (9H, s),1.51-1.83 (5H, m), 2.73 (1H, t d, J=7.0, 3.0 Hz), 3.94 (1H, m), 3.96(3H, s), 5.02 (2H, d, J=1.0 Hz), 5.76 (1H, br s), 6.84 (1H, d, J=1.0Hz), 7.26 (4H, m), 7.55 (3H, m), 7.70 (2H, br s); MS m/z CI⁺ 489 (M+H⁺).

(ii)[2S,3S]-2-Phenyl-3-{[5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl]methyloxy}piperidinehydrochloride

A solution of HCl in ethanol (2 ml, 5N) was added to a stirred solutionof[2S,3S]-1-tert-butoxyearbonyl-2-phenyl-3-{[5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl]methyloxy}piperidine(51 mg) in dry ethanol. After 2 hours the solvent was removed underreduced pressure and the residue was recrystallised from ether/ethanolto afford[2S,3S]-2-phenyl-3-{[5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl]methyloxy}piperidinehydrochloride as white needles (12.2 mg), mp 126-127° C. ¹ H NMR (360MHz, D₂ O)δ1.65-1.80 (2H, m), 2.20 (1H, m), 2.40 (1H, m), 3.21 (1H, m),3.63 (1H, m), 3.92 (3H, s), 3.96 (1H, br s), 4.39 (1H, br s), 4.66 (1H,d, J=11.0 Hz), 4.94 (1H, d, J=11.0 Hz), 6.70 (1H, d, J=1.0 Hz), 6.90(1H, d, J=1.0 Hz), 7.05-7.16 (5H, m), 7.60 (1H, d, J=1.0 Hz), 7.73 (1H,s), 7.78 (1H, d, J=1.0 Hz); MS m/z CI⁺ 389 (M+H⁺).

EXAMPLE 1[2S,3S]-1-[(5-(Dimethylaminomethyl)-1H-[1,2,3]triazol-4-yl)methlyl-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidinehydrochloride

(i)[2S,3S]-1-(4-Chlorobut-2-yn-1-yl)-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidine

A solution of[2S,3S]-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidinehydrochloride (230 mg) in N,N-dimethylformamiide (2 ml) was slowly addedto a solution of 1,4-dichlorobut-2-yne (106 ml) and potassium carbonate(224 mg) in N,N-dimethylformamide (2.0 ml). The solution was stirred for18 hours at room temperature and the solvent removed under reducedpressure. To the residue was added water (40 ml) and the product wasextracted with ethyl acetate (3×10 ml). The combined organic fractionswere washed with water, saturated brine, dried over MgSO₄, filtered andthe solvent removed under reduced pressure. The residue was purified byMPLC (10% ethyl acetate/hexane) to give[2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidineas a yellow oil (205 mg). ¹ H NMR (360 MHz,CDCl₃) δ1.57 (2H, m), 2.22(2H, m), 2.98 (1H, m), 3.27 (2H, d, J=3.0 Hz), 3.43 (1H, br s), 3.62(1H, br s), 3.95 (3H, s), 4.13 (2H, s), 4.46 (1H, d, J=11.0 Hz), 4.82(2H, d, J=11.0 Hz), 6.77 (1H, d, J=1.0 Hz), 6.87 (1H, s), 7.15 (3H, m),7.38 (2H, m), 7.43 (1H, s), 7.62 (2H, br s); MS m/z (CI⁺) 475 (M+H⁺).

ii)[2S,3S]-1-(4-Azidobut-2-yn-1-yl)-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidine

To a solution of[2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidine(205 mg) in dimethyl sulphoxide (3.0 ml) was added sodium azide (32.5mg). The solution was stirred for 20 hours at room temperature at whichtime aqueous ammonium chloride and ethyl acetate were added. The organicphase was separated, washed with water (20 ml), saturated brine (20 ml)dried over MgSO₄, filtered and the solvent removed under reducedpressure to give[2S,3S]-1-(4-azidobut-2-yn-1-yl)-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofaran-7-yl)methyloxy]piperidineas a white solid (120 mg). 1H NMR (360 MHz,CDCl₃)δ1.20-1.60 (2H, m),2.22 (2H, m), 2.67 (1H, m), 2.98 (1H, m), 3.27 (2H, m), 3.47 (1H, br s),3.62 (1H, br s), 3.91 (2H, s), 3.95 (3H, s), 4.47 (1H, d, J=11.0 Hz),4.81 (1H, d, J=11.0 Hz), 6.77 (1H, d, J=1.0 Hz), 6.87 (1H, s), 7.15 (3H,m), 7.38 (2H, m), 7.43 (1H, s), 7.62 (2H, br s); MS m/z (CI⁺) 482 M+H⁺).

iii)[2S,3S]-1-[(5-(Dimethylaminomethyl)-1H-[1,2,3]triazol-4-yl)methyl]-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidinehydrochloride

Dimethylamine (approximately 10 ml) was condensed at -80° C. in apressure tube and to this was added a solution of(2S,3S]-1-(4-azidobut-2-yn-1-yl)-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidine(120 mg) in dioxan (5 ml). The tube was sealed and the solution washeated at 80° C. for 14 hours. The solvent was evaporated under reducedpressure to dryness and the residue was purified by MPLC [5% methanol indichloromethane containing 0.25% ammonia (SG. 0.88)] to give[2S,3S]-1-[(5-dimethylaminomethyl)-1H[1,2,3]-triazol-4-yl)methyl]-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidineas a clear oil (47 mg). To a solution of this residue in diethyl etherwas added 5M-HCl in ethanol. The solution was evaporated to dryness andthe residue recrystallised from ether/ethanol to give[2S,3S]-1-[(5-(Dimethylaminomethyl)-1H-[1,2,3]triazol-4-yl)methyl]-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidinehydrochloride (57 mg) mp 136-138° C. ¹ H NMR (360 MHz,D₂ O)δ1.64 (1H,m), 1.87 (1H, m), 2.34 (2H, m), 2.65 (6H, s), 3.27 (1H, d, J=14.0 Hz),3.71-3.78 (3H, m), 3.85 (1H, br s), 3.93 (3H, s), 4.24 (1H, s), 4.33(1H, d, J=16.0 Hz), 4.38 (1H, d, J=16.0 Hz), 4.69 (1H, d, J=14.0 Hz),5.00 (1H, d, J=14.0 Hz), 6.79 (1H, s), 6.92 (1H, d, J=1.0 Hz), 7.16 (5H,m), 7.63 (1H, s), 7.74 (1H, s), 7.81 (1H, d, J=1.0 Hz); m/z (CI⁺) 527(M+H⁺).

We claim:
 1. A compound of the formula (I): ##STR31## wherein R¹ isphenyl or a 5- or 6-membered aromatic heterocyclic group containing 1,2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, whicharyl or heteroaryl group is optionally substituted by one or twosubstituents selected from halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, OCF₃,NO₂, CN, SR^(a), SOR^(a), SO₂ R^(a), COR^(a), CO₂ R^(a), (CH₂)_(n)CONR^(a) R^(b), (CH₂)_(n) NR^(a) R^(b) or (CH₂)_(n) NR^(a) COR^(b),where R^(a) and R^(b) are independently hydrogen or C₁₋₄ alkyl and n iszero, 1 or 2;R² is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃,OCF₃, N₂ O, CN, SR^(a), SOR^(a), SO₂ R^(a), CO₂ R^(a), CONR^(a) R^(b),C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₁₋₄ alkyl substituted by C₁₋₄ alkoxy,where R^(a) and R^(b) each independently represent hydrogen or C₁₋₄alkyl; R⁴ is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, CF₃, N₂ O, CN,SR^(a), SOR^(a), SO₂ R^(a), CO₂ R^(a), CONR^(a) R^(b), C₂₋₆ akenyl, C₂₋₆alkynyl or C₁₋₄ alkyl substituted by C₁₋₄ alkoxy, where R^(a) and R^(b)each independently represent hydrogen or C₁₋₄ alkyl; R⁵ is hydrogen,halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy substituted by C₁₋₄ alkoxy or CF₃ ; R⁶is a 5-membered or 6-membered heterocyclic ring containing 2 or 3nitrogen atoms optionally substituted by ═O, ═S or a C₁₋₄ alkyl group,and optionally substituted by a group of the formula ZNR⁷ R⁸ where Z isC₁₋₆ alkylene or C₃₋₆ cycloalkylene; R⁷ is hydrogen, C₁₋₄ alkyl, C₃₋₇cycloalkyl or C₃₋₇ cycloalkylC₁₋₄ alkyl, or C₂₋₄ alkyl substituted byC₁₋₄ alkoxy or hydroxyl; R⁸ is hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl orC₃₋₇ cycloalkylC₁₋₄ alkyl, or C₂₋₄ alkyl substituted by one or twosubstituents selected from C₁₋₄ alkoxy, hydroxyl or a 4, 5 or 6 memberedheteroaliphatic ring containing one or two heteroatoms selected from N,O and S; or R⁷, R⁸ and the nitrogen atom to which they are attached forma heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted byone or two groups selected from hydroxy or C₁₋₄ alkyl optionallysubstituted by a C₁₋₄ alkoxy or hydroxyl group, and optionallycontaining a double bond, which ring may optionally contain an oxygen orsulphur ring atom, a group S(O) or S(O)₂ or a second nitrogen atom whichwill be part of a NH or NR^(c) moiety where R^(c) is C₁₋₄ alkyloptionally substituted by hydroxy or C₁₋₄ alkoxy; or R⁷, R⁸ and thenitrogen atom to which they are attached form a non-aromatic azabicyclicring system of 6 to 12 ring atoms; or Z, R⁷ and the nitrogen atom towhich they are attached form a heteroaliphatic ring of 4 to 7 ring atomswhich may optionally contain an oxygen ring atom; R^(9a) and R^(9b) areeach independently hydrogen or C₁₋₄ alkyl, or R^(9a) and R^(9b) arejoined so, together with the carbon atoms to which they are attached,there is formed a C₅₋₇ ring; the dotted line is an optional double bond;A is --CH₂ --; Q¹ is oxygen, sulphur or --NH--; Q² is --N═, --NH--,--CH═ or --CH₂ --; X is an alkylene chain of 1 to 4 carbon atoms; Y ishydrogen or a C₁₋₄ alkyl group optionally substituted by a hydroxylgroup; and m is zero or 1; or a pharmaceutically acceptable salt andprodrug thereof.
 2. A compound as claimed in claim 1 of the formula (Ia)or a pharmaceutically acceptable salt or prodrug thereof: ##STR32##wherein A, X, Y, R¹, R², R⁶, Q¹, Q² and the dotted line are as definedin claim 1 and A¹ is fluorine or hydrogen.
 3. A compound a claimed inclaim 1 of the formula (Ib) or a pharmaceutically acceptable saltthereof: ##STR33## wherein A, Z, R¹, R², R⁷, R⁸, Q¹, Q², the dotted lineand m are as defined in claim 1, A¹ is fluorine or hydrogen and Y¹ ishydrogen or methyl.
 4. A compound as claimed in of claim 1 of theformula (Ic) or a pharmaceutically acceptable salt thereof: ##STR34##wherein R¹, R⁷, R⁸ and Z are as defined in claim 3, A¹ is fluorine orhydrogen and Y¹ is hydrogen or methyl.
 5. A compound as claimed in claim1 of the formula (Id) or a pharmaceutically acceptable salt or prodrugthereof: ##STR35## wherein A, X, Y, Q¹, Q², R¹, R², R⁴, R⁵, R⁶, R^(9a),R^(9b), m and the dotted line are as defined in claim
 1. 6. A compoundas claimed in claim 1 wherein X represents CH₂, CH(CH₃) or CH₂ CH₂.
 7. Acompound as calimed in claim 1 wherein R⁶ represents a heterocyclic ringselected from: ##STR36## wherein Z, R⁷ and R⁸ are as defined in claim 1.8. A compound as claimed in claim 1 wherein Z is CH₂ or CH₂ CH₂ and NR⁷R⁸ is amino, methylamino, dimethylamino, diethylamino, azetidinyl,pyrrolidino and morpholino.
 9. A compound as claimed in claim 1 whereinR¹ is the group ##STR37## where R¹⁰ is halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,CF₃, OCF₃, N₂ O, CN, SR^(a), SOR^(a), SO₂ R^(a), COR^(a), CO₂ R^(a),(CH₂)_(n) CONR^(a) R^(b), (CH₂)_(n) NR^(a) R^(b) or (CH₂)_(n) NR^(a)COR^(b), where R^(a) and R^(b) are hydrogen or C₁₋₄ alkyl, and n iszero, 1 or
 2. 10. A compound as claimed in claim 1 wherein Q¹ is anoxygen atom, Q² is --CH═ or --CH₂ --, and the dotted line represents adouble bond.
 11. A compound selectedfrom:[2S,3S]-1-[(5-(dimethylaminomethyl)-1H-[1,2,3]triazol-4-yl)methyl]-2-phenyl-3-[[5-(1-methyl-1H-1,2,3-triazol-5-yl)benzofuran-7-yl]methyloxy]piperidine;[2S,3S]-1-[(5-(dimethylaminomethyl)-1H-[1,2,3]triazol-4-yl)methyl]-2-phenyl-3-[(5-(5-methyl-1H-tetrazol-1-yl)benzofuran-7-yl)methyloxy]piperidine;or a pharmaceutically acceptable salt or prodrug thereof.
 12. Apharmaceutical composition comprising a therapeutically effective amountof a compound as claimed in claim 1 in association with apharmaceutically acceptable carrier or excipient.
 13. A method for thetreatment or prevention of pain or inflammation which comprisesadministration to a patient in need thereof of an effective amount ofthe compound of claim
 1. 14. A method for the treatment or prevention ofmigraine which comprises administration to a patient in need thereof ofan effective amount of the compound of claim
 1. 15. A method for thetreatment or prevention of emesis which comprises administration to apatient in need thereof of an effective amount of the compound ofclaim
 1. 16. A method for the treatment or prevention of postherpeticneuralgia which comprises administration to a patient in need thereof ofan effective amount of the compound of claim
 1. 17. A process for thepreparation of a compound as claimed in claim 1 which comprises:(A)reaction of a compound of formula (II) ##STR38## wherein R¹, R², R⁴, R⁵,R^(9a), R^(9b), A, Y, Q¹, Q², the dotted line and m are as defined inclaim 1, with a compound of formula (III):

    X.sup.1 --X--R.sup.6a                                      (III)

where X is as defined in claim 1, R^(6a) is a group of the formula R⁶ asdefined in claim 1 or a precursor therefor and X¹ is a leaving group;and, if R^(6a) is a precursor group, converting it to a group R⁶ ; or(B), for compounds of formula (I) wherein R⁶ represents1,2,3-triazol-4-yl substituted by CH₂ NR⁷ R⁸, and X is --CH₂ --,reaction of a compound of formula (IV) ##STR39## with an azide, followedby reduction of the carbonyl group adjacent to --NR⁷ R⁸ using a suitablereducing agent; or (C), for compounds of formula (I) wherein R⁶represents 1,2,3-triazol-4-yl substituted by CH2NR⁷ R⁸, and X is --CH₂--, reaction of a compound of formula (V) ##STR40## with an amine offormula NHR⁷ R⁸ ; or (D), for compounds of formula (I) wherein R⁶represents substituted or unsubstituted 1,3,5-triazine, reaction ofintermediates of formula (VI): ##STR41## with substituted orunsubstituted 1,3,5-triazine; or (E), for compounds of formula (I)wherein R⁶ represents substituted or unsubstituted 1,2,4-triazine,reaction of an intermediate of formula (VII) with a dicarbonyl compoundof formula (VIII): ##STR42## wherein R³⁵ represents H or a suitablesubstituent such as ZNR⁷ R⁸ ; or (F), for compounds of formula (I)wherein R⁶ represents a substituted 1,2,4-triazolyl group, reaction ofan intermediate of formula (II) with a compound of formula (IX)##STR43## wherein X is as defined in claim 1, Hal is a halogen atom, andR¹⁸ is H, CONH₂ or OCH₃ (which is converted to an oxo substituent underthe reaction conditions), in the presence of a base, followed wherenecessary by conversion to a compound of formula (I); or (G), forcompounds of formula (I) wherein R⁶ represents thioxotriazolyl, reactionof an intermediate of formula (X) ##STR44## with a compound of formulaHNCS, in the presence of a base; or (H), for compounds of formula (I)wherein the heterocycle R⁶ is substituted by ZNR⁷ R⁸, reaction of anintermediate of formula (II) as defined above with one of the compoundsof formula (XI): ##STR45## wherein each LG, which may be the same ordifferent, is a leaving group, and X and Z are as defined in claim 1,followed by reaction of the resultant compound with an amine NHR⁷ R⁸ tocomplete the ZNR⁷ R⁸ moiety; or (J), reaction of intermediates offormula (XII) ##STR46## wherein LG is a leaving group, with a compoundof formula (XIII)

    R.sup.1 --(CH.sub.2).sub.m --R.sup.40                      (XIII)

wherein R⁴⁰ is B(OH)₂ or Sn(alkyl)₃, in the presence of a palladiumcatalyst; or (K), for compounds of formula (I) wherein R¹ is atetrazol-1-yl group and m is zero, reaction of intermediates of formula(XIV) ##STR47## with ammonium chloride and sodium azide at elevatedtemperature; each process being followed, where necessary, by theremoval of any protecting group where present; and when the compound offormula (I) is obtained as a mixture of enantiomers or diastereoisomers,optionally resolving the mixture to obtain the desired enantiomer;and/or, if desired, converting the resulting compound of formula (I) ora salt thereof, into a pharmaceutically acceptable salt or prodrugthereof.